tbuckley/cabot-search huggingface dataset:
Real-world evaluation of the association between baseline metastatic patterns and clinical outcomes among patients with BRAF-positive metastatic melanoma.
Authors: Zeynep Eroglu, Sunandana Chandra, Elizabeth Iannotti Buchbinder, You-Li Ling, Jackson Tang, Rohan Shah, Thach-Giao Truong
Journal: Journal of Clinical Oncology (2022)

9532 Background: While immunotherapy (IO) and BRAF-targeted therapy (TT) have benefit in BRAFV600 mutant (BRAF+) metastatic melanoma (MM), there is a paucity of real-world data on the impact of systemic therapy choice on outcomes based on key characteristics such as site and number of baseline metastases. Patients with &gt;1 baseline site and certain sites of metastases are also underrepresented or excluded in clinical trials. The aim of this study was to evaluate the association between these characteristics and survival among BRAF+ MM patients. Methods: This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) dataset – harmonized customized data from Flatiron and ConcertAI. It included patients ≥18 years, who received treatment with a first-line (1L) IO (anti-PD-1 mono or combination therapy ipilimumab + nivolumab) or TT (any BRAF/MEK-inhibitors) after 1/1/2014. Progression free survival (PFS) and overall survival (OS) for IO and TT were analyzed according to number (1, 2, 3+ sites) and location (brain, lung, liver, bone) of baseline metastasis. Treatment sequence from 1L to 2L (i.e. IO/TT vs TT/IO) were also compared for PFS and OS outcomes. Results: A total of 1,961 patients were included, with 620 patients (32%) on IO monotherapy, 501 patients (26%) on IO combo therapy, and 840 patients (43%) on TT in the 1L. When adjusted for sex, age, ECOG, and Charlson Comorbidity Index, there was no difference in PFS or OS between 1L IO mono, IO combo and TT therapies in patients who had 1, 2, or 3+ baseline metastases. For patients who had either baseline brain, liver, lung, or bone metastasis, there was no difference in PFS and OS between IO mono, IO combo, and TT combo therapies. Of the 521 patients included in the sequencing analysis (only patients who received 2L therapy), 239 patients (46%) had 1L IO/2L TT. There was no difference in PFS or OS between treatment sequences for patients with any number or location of baseline metastasis. Conclusions: In this real-world retrospective cohort study, there is no difference in survival between 1L TT and IO for BRAF+ MM patients. Outcomes are comparable regardless of number and location of metastases, including brain metastasis. Whether switching from 1L TT to IO before progression may account for differences compared to trial data will be explored further.[Table: see text]
Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer
Authors: Marla Lipsyc-Sharf, Elza C. de Bruin, Katheryn Santos, Robert McEwen, Daniel Stetson, Ashka Patel, Gregory J. Kirkner, Melissa E. Hughes, Sara M. Tolaney, Ann H. Partridge, Ian E. Krop, Charlene Knape, Ute Feger, Giovanni Marsico, Karen Howarth, Eric P. Winer, Nancy U. Lin, Heather A. Parsons
Journal: Journal of Clinical Oncology (2022)

To examine the prevalence and dynamics of circulating tumor DNA (ctDNA) and its association with metastatic recurrence in patients with high-risk early-stage hormone receptor-positive breast cancer (HR+ BC) more than 5 years from diagnosis.We enrolled 103 patients with high-risk stage II-III HR+ BC diagnosed more than 5 years prior without clinical evidence of recurrence. We performed whole-exome sequencing (WES) on primary tumor tissue to identify somatic mutations tracked via a personalized, tumor-informed ctDNA test to detect minimal residual disease (MRD). We collected plasma at the time of consent and at routine visits every 6-12 months. Patients were followed for clinical recurrence.In total, 85 of 103 patients had sufficient tumor tissue; of them, 83 of 85 (97.6%) patients had successful whole-exome sequencing. Personalized ctDNA assays were designed targeting a median of 36 variants to test 219 plasma samples. The median time from diagnosis to first sample was 8.4 years. The median follow-up was 10.4 years from diagnosis and 2.0 years from first sample. The median number of plasma samples per patient was two. Eight patients (10%) had positive MRD testing at any time point. Six patients (7.2%) developed distant metastatic recurrence, all of whom were MRD-positive before overt clinical recurrence, with median ctDNA lead time of 12.4 months. MRD was not identified in one patient (1.2%) with local recurrence. Two of eight MRD-positive patients had not had clinical recurrence at last follow-up.In this prospective study, in patients with high-risk HR+ BC in the late adjuvant setting, ctDNA was identified a median of 1 year before all cases of distant metastasis. Future studies will determine if ctDNA-guided intervention in patients with HR+ BC can alter clinical outcomes.
Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave—Reply
Authors: Caroline Maslo, Mande Toubkin
Journal: JAMA (2022)

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An update on the overall epidemiology, clinical characteristics, and outcomes from the COVID-19 and Cancer Consortium (CCC19).
Authors: Dimpy P Shah, Pankil Shah, Jeremy Lyle Warner, Gerald Batist, Christopher Ryan Friese, Elizabeth A. Griffiths, Clara Hwang, Kendra Vieira, Rana R. McKay, Ruben A. Mesa, Matthew Puc, Elizabeth M Robilotti, Erika Ruiz-Garcia, Andrew Jay Portuguese, Andrew Lachlan Schmidt, Lisa B. Weissmann, Trisha Michel Wise-Draper, Jill Barnholtz-Sloan, Solange Peters, Petros Grivas
Journal: Journal of Clinical Oncology (2022)

10565 Background: Despite mitigation and treatment strategies, COVID-19 continues to negatively impact patients (pts) with cancer. Identifying factors that remain consistently associated with morbidity and mortality is critical for risk identification and care delivery. Methods: Using CCC19 registry data through 12/31/2021 we report clinical outcomes (30-day case fatality rate [CFR], mechanical ventilation use (MV), intensive care unit admission (ICU), and hospitalization) in adult pts with cancer and laboratory confirmed SARS-CoV-2, stratified by patient, cancer, and treatment-related factors. Results: In this cohort of 11,417 pts (with 4% reported vaccination prior to COVID-19), 55% required hospitalization, 15% ICU, 9% MV, and 12% died. Overall outcome rates remained similar for 2020 and 2021 (Table). Hydroxychloroquine was utilized in 11% and other anti-COVID-19 drugs (remdesivir, tocilizumab, convalescent plasma, and/or steroids) in 30%. Higher CFRs were observed in older age, males, Black race, smoking (14%), comorbidities (pulmonary [17%], diabetes mellitus [16%], cardiovascular [19%], renal [21%]), ECOG performance status 2+ (31%), co-infection (25%), especially fungal (35%), and initial presentation with severe COVID-19 (48%). Pts with hematologic malignancy, active/progressing cancer status, or receiving systemic anti-cancer therapy within 1-3 months prior to COVID-19 also had worse CFRs. CFRs were similar across anti-cancer modalities. Other outcomes (ICU, MV, hospitalization) followed similar distributions by pt characteristics. Conclusions: Unfavorable outcome rates continue to remain high over 2 years, despite fewer case reports in 2021 owing to multiple factors (e.g., pandemic dynamics, respondent fatigue, overwhelmed healthcare systems). Pts with specific socio-demographics, performance status, comorbidities, type and status of cancer, immunosuppressive therapies, and COVID-19 severity at presentation experienced worse COVID-19 severity; and these factors should be further examined through multivariable modeling. Understanding epidemiological features, patient and cancer-related factors, and impact of anti-COVID-19 interventions can help inform risk stratification and interpretation of results from clinical trials. [Table: see text]
Impact of site-specific metastases on survival outcomes in pancreatic adenocarcinoma (PDAC) patients: A national analysis.
Authors: Nima Nikravesh, Gillian Gresham, Eric Anderson, Omer Elmadbouh, Shant Thomassian, Natalie Moshayedi, John Davelaar, Simon Lo, Srinivas Gaddam, Nicholas Nissen, Kambiz Kosari, Alexandra Gangi, Stephen Jacob Pandol, Jun Gong, Andrew Eugene Hendifar, Arsen Osipov
Journal: Journal of Clinical Oncology (2022)

e16270 Background: PDAC is the third most fatal cancer, where most patients present with metastases at diagnosis. Previous studies, including a retrospective analysis from our single-center experience, suggests survival rates are significantly higher for those with lung-only metastases (mets) when compared to liver metastasis or other sites of metastases (liver+other). The objective of this analysis is to explore this difference based on sites and metastasis and the impact of chemotherapy from a national cohort. Methods: We identified PDAC patients (&gt;18years) from with metastases to either 1) lung-only; 2) liver+other sites in the National Cancer Database diagnosed between 2010 and 2015.We analyzed patient characteristics, demographics, type of chemotherapy, and survival outcomes. Kaplan Meir survival curves were generated, and Cox proportional hazard models adjusted for age and sex were fit to evaluate associations between met site and survival. Survival was calculated from time of diagnosis to death and compared across mets site, receipt of chemotherapy, and treatment and type (single versus multi-agent). Results: 15359 PDAC patients were included in the analysis [51.6% male 48.4% female, mean age 69 years] of which 4512 (29.4%) patients had lung only mets and 10847 (70.6%) had liver + other mets. Median survival was 5.72 and 2.37 months for lung only vs. liver+other mets, respectively (log rank p&lt;0.001). From a subset population of 8440 patients who received chemotherapy, median survival of 9.4 and 4.9 months for lung only and liver+other mets was observed, respectively [Table]. Median OS for single agent chemotherapy was 4.4 months (n=2637), with patients with lung only mets having a median OS of 7.1 months and those with liver+other mets having a median OS of 3.6 months. Median OS for patients treated with multi-agent chemotherapy (n=5380) was 7.4 months, with lung only met patients having a median OS of 11.6 months and those with liver+other mets having a median OS of 6.1 months. Hazard ratios (HR) and 95% confidence intervals (CI) are displayed in the table. Conclusions: In a national cohort, patients with metastatic PDAC and lung-only metastasis had improved survival when compared with liver +other metastasis. Further contemporary research is needed to understand the underlying biology that dictates the survival difference between lung metastasis vs other sites of metastatic disease in pancreatic cancer.[Table: see text]
Sacubitril/valsartan in an experimental model of heart failure with preserved ejection fraction
Authors: A De Angelis, D Cappetta, M Telesca, G Bellocchio, K Urbanek, L Berrino
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry for Education, University and Research Introduction The majority of elderly patients with heart failure has a preserved ejection fraction (HFpEF) that constitutes a syndrome characterized by frequent hospitalizations and high mortality. Despite the growing social burden of HFpEF, the comprehension of its pathophysiology is incomplete, and treatment remains largely undefined. Aging itself may contribute independently to deterioration of diastolic function. Methods 18-month old female Fischer 344 rats were treated with oral administration of either sacubitril/valsartan (60 mg/kg/die, 1:1 ratio) or valsartan alone (30 mg/kg/die) for 12 weeks. Tail-cuff method was used to monitor blood pressure weekly. Echocardiography and left ventricle catheterization were employed to assess systolic and diastolic function, at baseline, and before sacrifice. Cardiac tissue was used for molecular biology and histochemistry assays. Results Tail-cuff analysis indicated a comparable decrease in blood pressure between treatments. Hypertrophy also showed a significant reduction with both treatments. On the contrary, myocardial function analysis demonstrated that no treatment was efficacy on diastolic dysfunction. The lack of improvement of cardiac function could be attributed to the inability of the treatments to counteract the accumulation of fibrotic tissue in the left ventricle, which, in turn, is attributable to the failure to reduce the inflammatory process and oxidative stress, and to the inability to modulate angiotensin II pathway. Conclusion Our results evidenced that both sacubitril/valsartan or valsartan treatment was able to improve diastolic function and pro-fibrotic remodeling, partly due to a lack of effect on classical and non-classical pathways of angiotensin II.
NFB-18. Integration of single-nuclei RNA-sequencing and spatial transcriptomics to define the complex tumor microenvironment of NF1-associated plexiform neurofibroma and highly-aggressive malignant peripheral nerve sheath tumors
Authors: Vladimir Amani, Andrew Donson, Kent Riemondy, Rui Fu, Nicholas Willard, Ahmed Gilani, Gregory Norris, Andrea Griesinger, Faith Harris, Enrique Grimaldo, Nicholas Foreman
Journal: Neuro-Oncology (2022)

Abstract During formation of plexiform neurofibroma (PN), a complex tumor microenvironment (TME) develops, with recruitment of other cell types being critical for growth and progression. Approximately 10% of PN can undergo transformation into malignant peripheral nerve sheath tumors (MPNST) which is a substantial cause of mortality in older teenagers and young adults. We sought to apply single cell transcriptomic analysis to PN and MPNST to provide a clearer understanding of the complex TME and how this contributes to transformation and disease progression. Due to the cohesive cellularity of PN, single-cell RNA-sequencing is difficult and may result in a loss of detection of critical cellular subpopulations. Single-nuclei RNA-sequencing (snRNA-seq) is an alternative approach that can be applied to fibrous and bulk frozen tissues, such as NF1-associated PN. Our initial snRNA-seq analysis of PN indicates that PN have a TME comprised of a variety of cellular subpopulations, with the predominant fraction being fibroblast-like cells. snRNA-seq analysis of MPNST also shows high cellular heterogeneity, including distinct fibroblast-like subpopulations distinct from PN fibroblast clusters, increased proliferating populations and antigen presenting cells. MPNST cluster separately from PN, suggesting an evolutionary shift in tumor biology. We are currently validating our findings using Visium spatial transcriptomic profiling, allowing us to apply TME architectural context to the PN and MPNST subpopulations identified by snRNA-seq. These techniques provide a deeper understanding of the complex cellular heterogeneity of human PN and MPNST that has not previously been used to describe the TME of these tumors. The mechanisms of tumorigenesis and malignancy described can provide targets for novel therapies ultimately benefitting patients with these devastating tumors of childhood and early adulthood.
LGG-47. Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity During Malignant Progression in Glioma
Authors: Sakthi Rajendran, Clayton Peterson, Alessandro Canella, Yang Hu, Amy Gross, Maren Cam, Akdes Serin-Harmanci, Rosario Distefano, Giovanni Nigita, Wesley Wang, Mark Hester, Katherine Miller, Olivier Elemento, Ryan Roberts, Eric Holland, Ganesh Rao, Elaine Mardis, Prajwal Rajappa
Journal: Neuro-Oncology (2022)

Abstract Myeloid cells and macrophages have been shown to promote immunosuppression in high-grade gliomas (HGG), however their roles in malignant progression of low-grade glioma (LGG) are poorly understood. Here, we investigated the heterogeneity of the immune microenvironment during glioma progression using a murine model that recapitulates the malignant progression of low to high-grade glioma. To that end, we performed single-cell RNA sequencing on CD45+ immune cells isolated from animals bearing no tumor (NT), LGG, and HGG. We observed an increased infiltration of CD4+ T cells, CD8+ T cells, B cells, and natural killer cells in the tumor microenvironment of LGG, whereas this infiltration was abrogated in HGG. Our study identified two distinct macrophage clusters across all 3 samples, with signatures of bone marrow derived and resident macrophages, respectively. These macrophages showed an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG, but then evolved to a more immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG, restricting T cell recruitment and activation. In addition, we identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for both these distinct macrophage populations, based on their increased expression in LGG and HGG compared to NT. Targeting these factors during the LGG therapeutic window may inhibit myeloid cells and intra-tumoral macrophages and attenuate their immunosuppressive properties and impair malignant progression.
Russia’s status as WHO member under threat after World Health Assembly vote
Authors: Owen Dyer
Journal: BMJ (2022)

Russia's role in the World Health Organization was under threat from two directions following two defeats at the annual World Health Assembly (WHA) in Geneva.A motion drafted by Ukraine condemning Russian attacks on health infrastructure passed easily, while a Russian and Syrian counter motion that sought to share the blame was soundly rejected.1 Ukraine and 40 co-sponsor nations.WHA draft resolution: health emergency in Ukraine and refugee receiving and hosting countries, stemming from the Russian Federation's aggression.23 May 2022.
Do patients with metastatic pancreatic adenocarcinoma to the lung have improved survival?
Authors: Aren Ebrahimi, Melanie Shadarevian, Jason Cham, David Jacob Hermel, Samantha R. Spierling Bagsic, Darren Sigal
Journal: Journal of Clinical Oncology (2022)

e16257 Background: Pancreatic ductal adenocarcinoma (PDAC) is a genetically heterogeneous disease often diagnosed with synchronous metastatic disease involving the liver. Tumors with extra-abdominal spread that bypass the liver are thought to represent a unique molecular subgroup of the disease. Specifically, those with isolated pulmonary metastatic disease are thought to have a more favorable clinical phenotype. We sought to retrospectively investigate whether patients with isolated pulmonary metastases had improved survival compared to those with disease involving the liver. Methods: We conducted a retrospective review of patients with pathologically confirmed PDAC treated between the years 2010 and 2020 at a Scripps Health hospital. The final study sample included only patients with pulmonary and/or liver primary metastases (N = 175). Analyses were conducted on subgroups defined by metastatic sites of disease in the liver only, lung only and combined liver+lung. Primary and secondary outcome analyses compared isolated lung versus liver/liver+lung. Primary endpoint was overall survival (OS), defined as from the date of diagnosis to date of death or most recent follow up. Progression free survival (PFS) was also analyzed as a secondary endpoint and defined as from the date of diagnosis to date of radiographic progression. Each survival outcome was analyzed using Cox Proportional Hazards tests. Results: No statistically significant differences were seen in OS (HR 0.67, CI 0.44–1.03; p= 0.069) or PFS (HR 1.05, CI 0.68–1.65; p= 0.816) between patients with primary lung metastases compared to those with either liver or liver+lung metastases (reported as hazard ratios of liver/liver+lung relative to lung only). However, a trend towards improved OS was seen for patients with isolated lung metastasis and the kaplan-meier curve for OS showed improved survival for these patients at 3 years, with crossing of the survival curves around 5 years from time of diagnosis. Conclusions: There appears to be a unique clinical phenotype in patients with PDAC presenting with isolated pulmonary disease. Though there was not a statistically significant difference in OS and PFS seen in our population, there was a trend towards improved overall survival compared to those with hepatic involvement. These findings highlight a potential prognostic indicator of metastatic PDAC and further subgroup analysis will help characterize clinical variations that may lead to these differences in tumor biology.[Table: see text]